Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.

Abstract

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

DOI: 10.1038/mt.2008.281
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@article{Mahdy2009AcidCU, title={Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.}, author={Ayman E M Mahdy and Joseph C. K. Cheng and Jun Li and Saeed Elojeimy and William D Meacham and Lorianne Stehouwer Turner and Aiping Bai and Christopher R Gault and Alex S McPherson and Nicole Garcia and Thomas H. Beckham and Antonio F. Saad and Alicja Bielawska and Jacek Bielawski and Yusuf A. Hannun and Thomas E. Keane and Mohhammed I Taha and Hisham M. Hammouda and James Norris and Xiang Liu}, journal={Molecular therapy : the journal of the American Society of Gene Therapy}, year={2009}, volume={17 3}, pages={430-8} }